摘要
OBJECTIVE@#To observe the effect of electroacupuncture (EA) at "Zusanli" (ST 36) combined with mosapride on gastric emptying rate and gastric motility in the rats with diabetic gastroparesis.@*METHODS@#Using random number table method, 68 male SD rats were divided into a blank group (12 rats) and a model establishment group (56 rats). In the model establishment group, the models of diabetic gastroparesis were established with intraperitoneal injection of streptozotocin combined with high-fat and high-sugar diet. Six weeks later, the successful rat models in the model establishment group were randomized into a model group, an EA group, a mosapride group and a combined treatment group, 12 rats in each one. In the EA group, EA was exerted at "Zusanli" (ST 36) (disperse-dense wave, 2 Hz/15 Hz in frequency, 2 mA in intensity) for 20 min. In the mosapride group, mosapride was intervened with intragastric administration (2 mg/kg). In the combined treatment group, electroacupuncture at "Zusanli" (ST 36) was combined with intragastric administration of mosapride. The intervention was given once daily in each group. There was 1 day at interval after 6-day intervention, consecutively for 5 weeks. At the end of intervention, the random blood glucose, gastric emptying rate and the data of gastric motility (average intra-gastric pressure, amplitude and frequency of gastric motility) were detected.@*RESULTS@#Compared with the blank group, blood glucose was increased in the model group (P<0.001). Blood glucose was reduced in the EA group, the mosapride group and the combined treatment group as compared with the model group separately (P<0.001, P<0.01), whereas, compared with the mosapride group, blood glucose was decreased in the combined treatment group (P<0.05). In comparison with the blank group, the gastric emptying rate, the average intra-gastric pressure and the amplitude of gastric motility were all decreased in the model group (P<0.001) and the frequency of gastric motility was increased (P<0.001). Gastric emptying rate, the average intra-gastric pressure and the amplitude of gastric motility were increased in the EA group, the mosapride group and the combined treatment group (P<0.01, P<0.05, P<0.001) and the frequency of gastric motility was decreased (P<0.001) as compared with the model group respectively. Compared with the EA group, the average intra-gastric pressure and the amplitude of gastric motility were increased in the combined treatment group (P<0.001). In comparison with the mosapride group, the gastric emptying rate, the average intra-gastric pressure, the amplitude and frequency of gastric motility in the combined treatment group, as well as the frequency of gastric motility in the EA group were all increased (P<0.05, P<0.001, P<0.01).@*CONCLUSION@#Electroacupuncture at "Zusanli" (ST 36) combined with intragastric administration of mosapride could regulate blood glucose and improve the gastric motility in the rats with diabetic gastroparesis. The effect is better than either simple electroacupuncture or mosapride.
Subject(s)
Animals , Male , Rats , Acupuncture Points , Benzamides , Diabetes Mellitus/therapy , Electroacupuncture , Gastrointestinal Motility/physiology , Gastroparesis/etiology , Morpholines , Rats, Sprague-Dawley摘要
OBJECTIVE@#To investigate the inhibitory effect of AZD2014, a dual mTORC1/2 inhibitor, against acute graft rejection in a rat model of allogeneic liver transplantation.@*METHODS@#Liver transplantation from Lewis rat to recipient BN rat (a donor-recipient combination that was prone to induce acute graft rejection) was performed using Kamada's two-cuff technique. The recipient BN rats were randomized into 2 groups for treatment with daily intraperitoneal injection of AZD2014 (5 mg/kg, n=4) or vehicle (2.5 mL/kg, n=4) for 14 consecutive days, starting from the first day after the transplantation. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels of the rats were measured 3 days before and at 1, 3, 5, 7, 10, and 14 days after the transplantation, and the survival time of the rats within 14 days were recorded. Immunohistochemical staining was used to examine the expressions of CD3 and Foxp3 in the liver graft, and acute graft rejection was assessed using HE staining based on the Banff schema.@*RESULTS@#Three rats in the control group died within 14 days after the surgery, while no death occurred in the AZD2014 group, demonstrating a significantly longer survival time of the rats in AZD2014 group (χ2=4.213, P=0.04). Serum ALT, AST and TBIL levels in the control group increased progressively after the surgery and were all significantly higher than those in AZD2014 group at the same time point (P < 0.05). Pathological examination revealed significantly worse liver graft rejection in the control group than in AZD2014 group based on assessment of the rejection index (P < 0.01); the rats in the control group showed more serious T lymphocyte infiltration and significantly fewer Treg cells in the liver graft than those in AZD2014 group (P < 0.01).@*CONCLUSIONS@#AZD2014 can effectively inhibit acute graft rejection in rats with allogeneic liver transplantation.
Subject(s)
Animals , Rats , Benzamides , Graft Rejection/prevention & control , Graft Survival , Liver/pathology , Liver Transplantation , Mechanistic Target of Rapamycin Complex 1 , Morpholines , Pyrimidines , Rats, Inbred Lew摘要
Abstract The universal definition of myocardial infarction (MI) provides five subtypes of acute myocardial infarction (AMI). We present an interesting case of a type 2 myocardial infarction caused by the dilation of the left thoracic stomach.
Subject(s)
Humans , Male , Aged , Stomach/surgery , Gastric Dilatation/etiology , Anastomosis, Surgical/adverse effects , Esophagus/surgery , Inferior Wall Myocardial Infarction/etiology , Gastric Dilatation/drug therapy , Gastric Dilatation/diagnostic imaging , Benzamides/therapeutic use , Gastrointestinal Agents/therapeutic use , Morpholines/therapeutic use , Acute Disease , Esophagectomy/methods , Gastroparesis/etiology , Gastroparesis/drug therapy , Gastroparesis/diagnostic imaging , Coronary Stenosis/etiology , Coronary Stenosis/drug therapy , Coronary Stenosis/diagnostic imaging , Electrocardiography , Esophagus/diagnostic imaging , Inferior Wall Myocardial Infarction/diagnosis摘要
Abstract Background: Postoperative Nausea and Vomiting (PONV) is a common complication of general anesthesia. Several kinds of antiemetics, including 5-Hydroxytryptamine3 (5-HT3) receptor antagonists, and Neurokinin-1 (NK-1) receptor antagonists have been used to treat PONV. Objectives: To compare the antiemetic effect of NK-1 receptor antagonists, including fosaprepitant. Data sources: Online databases (PubMed, MEDLINE, Scopus, The Cochrane Library databases) were used. Study eligibility criteria, participants, and interventions: Randomized Controlled Trials (RCTs) performed in patients over 18 years with ASA-PS of I‒III, aimed to assess the efficacy of antiemetics including NK-1 receptor antagonists and 5-HT3 receptor antagonists, and compared the incidence of PONV were included. Study appraisal and synthesis methods: All statistical assessments were conducted by a random effect approach, and odds ratios and 95% Confidence Intervals were calculated. Results: Aprepitant 40 mg and 80 mg significantly reduced the incidence of vomiting 0‒24 hours postoperatively (Odds Ratio [OR = 0.40]; 95% Confidence Interval [95% CI 0.30‒0.54]; p < 0.001, and OR = 0.32; 95% CI 0.19‒0.56; p < 0.001). Fosaprepitant could also reduce the incidence of vomiting significantly both 0‒24 and 0‒48 hours postoperatively (OR = 0.07; 95% CI 0.02‒0.24; p < 0.001 and OR = 0.07; 95% CI 0.02‒0.23; p < 0.001). Limitations: Risk factors for PONV are not considered, RCTs using multiple antiemetics are included, RCTs for fosaprepitant is small, and some bias may be present. Conclusions and implications of key findings: Aprepitant and fosaprepitant can be effective prophylactic antiemetics for postoperative vomiting. However, more studies are required for higher-quality meta-analyses. Systematic review registration number: CRD42019120188.
Resumo Histórico: Náusea e Vômito no Pós-Operatório (NVPO) é um evento adverso frequente da anestesia geral. Várias classes de antieméticos, incluindo antagonistas do receptor 5-Hidroxitriptamina3 (5-HT3) e antagonistas do receptor da Neurocinina-1 (NK-1), têm sido utilizados para tratar a NVPO. Objetivo: Comparar o efeito antiemético dos antagonistas do receptor NK-1, incluindo o fosaprepitanto. Fontes de dados: Foram utilizadas bases de dados on-line (PubMed, MEDLINE, Scopus, The Cochrane Library). Critérios de elegibilidade do estudo, participantes e intervenções: Foram incluídos Estudos Clínicos Randomizados (ECR) realizados em pacientes acima de 18 anos classificação ASA I a III, com o objetivo de avaliar a eficácia de antieméticos que incluíssem antagonistas do receptor NK-1 e antagonistas do receptor 5-HT3, e que comparassem a incidência de NVPO. Métodos de avaliação e síntese do estudo: Todas as avaliações estatísticas foram realizadas por abordagem de efeito aleatório e foram calculadas razões de chances e Intervalos de Confiança de 95%. Resultados: As doses de 40 mg e 80 mg de aprepitanto reduziram significantemente a incidência de vômito no período de 0 a 24 horas pós-operatórias (razão de chances [OR = 0,40]; Intervalo de Confiança de 95% [95% IC] 0,30-0,54; p < 0,001 e OR = 0,32; 95% IC 0,19-0,56; p < 0,001). O fosaprepitanto pode também reduzir significantemente a incidência de vômito tanto de 0-24 horas como no período de 0-48 horas pós-operatórias (OR = 0,07; 95% IC 0,02-0,24; p < 0,001 e OR = 0,07; 95% IC 0,02-0,23; p < 0,001). Limitações: Os fatores de risco para NVPO não foram analisados, ECRs usando múltiplos antieméticos foram incluídos, ECRs para fosaprepitanto tinham amostras pequenas, podendo haver algum viés. Conclusões e implicações dos principais achados: Aprepitanto e fosaprepitanto podem ser drogas antieméticas profiláticas efetivas para vômito no pós-operatório. No entanto, são necessários mais estudos para elaboração de meta-análises de melhor qualidade. Número de registro da revisão sistemática: CRD42019120188.
Subject(s)
Humans , Postoperative Nausea and Vomiting/prevention & control , Neurokinin-1 Receptor Antagonists/administration & dosage , Antiemetics/administration & dosage , Randomized Controlled Trials as Topic , Morpholines/administration & dosage , Morpholines/pharmacology , Incidence , Postoperative Nausea and Vomiting/epidemiology , Serotonin 5-HT3 Receptor Antagonists/administration & dosage , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Neurokinin-1 Receptor Antagonists/pharmacology , Anesthesia, General/adverse effects , Anesthesia, General/methods , Antiemetics/pharmacology摘要
OBJECTIVE@#To study the effect of the focal adhesion kinase inhibitor TAE226 on epithelial-mesenchymal transition (EMT) in human oral squamous cell carcinoma (OSCC) cell line.@*METHODS@#HSC-3 and HSC-4 cells were cultured with TAE226 under different concentrations (0, 1, 5, and 10 μmol·L⁻¹) for 24, 48, and 72 h. Real-time quantitative polymerase chain reaction was performed to detect the mRNA expressions of E-cadherin and Vimentin. The protein expressions of E-cadherin and Vimentin were determined by Western blot assay after 48 h of TAE226 treatment.@*RESULTS@#Real-time quantitative polymerase chain reaction showed that increasing the TAE226 dose and reaction time resulted in increased and decreased E-cadherin and Vimentin mRNA expressions, respectively (P<0.05). Western blot assays showed that increasing the TAE226 dose resulted in increased and decreased E-cadherin and Vimentin protein expressions, respectively (P<0.05).@*CONCLUSIONS@#TAE226, which is expected to be an effective drug for OSCC treatment, can effectively inhibit the EMT of the OSCC cell line.
Subject(s)
Humans , Cadherins , Carcinoma, Squamous Cell , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Focal Adhesion Protein-Tyrosine Kinases , Morpholines , Mouth Neoplasms , Vimentin摘要
Phytophthora parasitica is an important oomycete that causes disease in a variety of plants, dimethomorph fungicides being specific for oomycetes. The aim of this study was to use RNA-seq to rapidly discover the mechanism by which dimethomorph acts in the treatment of P. parasitica. We found that the expression of 832 genes changed significantly after the dimethomorph treatment, including 365 up-regulated genes and 467 down-regulated genes. According to the Gene Ontology (GO) enrichment analysis, pathway enrichment and verification test results, the following conclusions are obtained: (i) the treatment of P. parasitica with dimethomorph causes changes in the expression levels of genes associated with the cell wall and cell wall synthesis; (ii) dimethomorph treatment results in reduced permeability of the cell membrane and changes in the expression of certain transport-related proteins; (iii) dimethomorph treatment increased reactive oxygen species and reduced the expression of genes related to the control of oxidative stress.
Phytophthora parasitica es un importante oomiceto que origina enfermedades en una variedad de plantas; el fungicida dimetomorf es específico contra oomicetos. El objetivo de este estudio fue utilizar la tecnología de RNA-seq para descubrir rápidamente el mecanismo por el que el dimetomorf actúa en el tratamiento de P. parasitica. Descubrimos que la expresión de 832 genes se modificaba significativamente tras el tratamiento con dimetomorf, incluyendo 365 genes que son sobrerregulados y 467 genes que son subrregulados. El análisis de enriquecimiento de ontología de genes (GO), análisis de enriquecimiento de las vías y pruebas de verificación permitieron extraer las conclusiones siguientes: 1) el tratamiento de P. parasitica con dimetomorf origina cambios en los niveles de expresión de los genes relacionados con la pared celular y su síntesis; 2) el tratamiento con dimetomorf origina una reducción de la permeabilidad de la membrana celular, así como cambios en la expresión de ciertas proteínas relacionadas con el transporte, y 3) el tratamiento con dimetomorf incrementó las especies reactivas del oxígeno y redujo la expresión de los genes relacionados con el control del estrés oxidativo.
Subject(s)
Phytophthora/drug effects , RNA, Messenger/biosynthesis , Morpholines/pharmacology , Fungicides, Industrial/pharmacology , RNA-Seq , Phytophthora/genetics , Plant Diseases/parasitology , RNA, Messenger/genetics , Carrier Proteins/biosynthesis , Carrier Proteins/genetics , Cell Membrane Permeability/drug effects , Cell Membrane Permeability/genetics , Cell Wall/metabolism , Gene Expression Regulation/drug effects , Sequence Alignment , Reactive Oxygen Species , Oxidative Stress/genetics , beta-Glucans/analysis , Real-Time Polymerase Chain Reaction , Gene Ontology摘要
OBJECTIVE@#To study the effects of the overexpression of autophagy-related gene 3 (ATG3) on autophagy and salinomycin-induced apoptosis in breast cancer cells and explore the underlying mechanisms.@*METHODS@#We used the lentivirus approach to establish a breast cancer cell line with stable overexpression of ATG3. Western blotting, immunofluorescence staining and transmission electron microscopy were used to analyze the effect of ATG3 overexpression on autophagy in breast cancer MCF-7 cells. Using the AKT/mTOR agonists SC79 and MHY1485, we analyzed the effect of AKT/mTOR signal pathway activation on ATG3 overexpression-induced autophagy. Western blotting and flow cytometry were used to analyze the effect of autophagy on apoptosis of the ATG3-overexpressing cells treated with salinomycin and 3-MA (an autophagy inhibitor).@*RESULTS@#In ATG3-overexpressing MCF-7 cells, ATG3 overexpression obviously promoted autophagy, inhibited the AKT/mTOR signaling pathway, significantly weakened salinomycin-induced apoptosis ( < 0.01), caused significant reduction of the levels of the pro-apoptotic proteins cleaved-caspase 3 ( < 0.01) and Bax ( < 0.05), and enhanced the expression of the anti-apoptotic protein Bcl-2 ( < 0.05). The inhibition of autophagy obviously weakened the inhibitory effect of ATG3 overexpression on salinomycin-induced apoptosis.@*CONCLUSIONS@#ATG3 overexpression promotes autophagy possibly by inhibiting the AKT/mTOR signaling pathway to decrease salinomycin-induced apoptosis in MCF-7 cells, suggesting that autophagy induction might be one of the mechanisms of drug resistance in breast cancer cells.
Subject(s)
Female , Humans , Acetates , Pharmacology , Apoptosis , Genetics , Autophagy , Autophagy-Related Proteins , Metabolism , Benzopyrans , Pharmacology , Breast Neoplasms , Metabolism , Pathology , Cell Line, Tumor , Cell Proliferation , Drug Resistance, Neoplasm , Gene Expression Regulation , MCF-7 Cells , Morpholines , Pharmacology , Proto-Oncogene Proteins c-akt , Metabolism , Pyrans , Pharmacology , TOR Serine-Threonine Kinases , Metabolism , Triazines , Pharmacology , Ubiquitin-Conjugating Enzymes , Metabolism摘要
The aim of this paper was to explore the mechanism of Shenxiong Glucose Injection antagonizing apoptosis of H9 c2 cells induced by H_2O_2. H9 c2 cells were pretreated with 1. 7%,3. 4% and 6. 8% Shenxiong Glucose Injection,and then H_2O_2 was introduced to induce apoptosis in vitro. Cell viability was detected by MTS assay,morphological changes of apoptosis were observed by AO/EB fluorescence staining,apoptosis rate was detected by Annexin/PI method,cell expression profile was detected by gene chip technology,the mRNA of PIK3 CA,Bcl-2,Bax,caspase-3 and GAPDH were detected by qRT-PCR,the protein expression levels of PIK3 CA,AKT,P-AKT,Bcl-2,Bax and caspase-3 were detected by Western blot,and the contents of LDH and MDA were detected by kit. The results showed that Shenxiong Glucose Injection of different concentrations significantly increased the viability of H9 c2 cells treated with H_2O_2( P<0. 01),and reversed H_2O_2-induced apoptosis( P< 0. 01). The microarray experiments showed that 138 genes were altered in H9 c2 cells after treatment with Shenxiong Glucose Injection. The differential expression fold of PIK3 CA associated with PI3 K/AKT pathway was 3. 59. The results of qRT-PCR and Western blot showed that Shenxiong Glucose Injection could down-regulate the mRNA and protein expression levels of caspase-3( P<0. 01),up-regulate the mRNA and protein expression level of PIK3 CA and Bcl-2( P<0. 01),and up-regulate the phosphorylation levels of AKT( P<0. 01) in H_2O_2-treated H9 c2 cells. The protective effect of Shenxiong Glucose Injection on H_2O_2 cells injury was significantly inhibited by LY294002,a PI3 K/AKT pathway inhibitor. The results suggested that Shenxiong Glucose Injection may inhibit H_2O_2-induced H9 c2 cells apoptosis by regulating PI3 K/AKT signaling pathway.
Subject(s)
Animals , Rats , Apoptosis , Cell Line , Chromones , Drugs, Chinese Herbal , Pharmacology , Glucose , Morpholines , Phosphatidylinositol 3-Kinases , Metabolism , Proto-Oncogene Proteins c-akt , Metabolism , Signal Transduction摘要
OBJECTIVE@#To investigate the anti-apoptotic effect of Angelica polysaccharide (APS) on cryopreservated platelets and its mechanism.@*METHODS@#The platelets were divided into 4 group: control group(4 ℃ stored platelets),APS group (APS-treated platelets stored at 4 ℃), LY294002 group (LY294002-treated platelets stored at 4 ℃) and LY294002+APS group(LY294002+APS treated platelets stored at 4 ℃ ). The expression of platelet membrane glycoprotein CD41 and CD61, as well as the platelet apoptotic rate, Caspase 3 expression and mitochondrial membrane potential (MMP) were detected by flow cytometry; the anti-apoptotic mechanism of APS by PI3K /AKT signaling pathway was analyzed by Western blot assay.@*RESULTS@#The apoptosis rate of platelets in LY294002 group obviously increased, the activity of CD41 and CD61 expression gradually decreased along with the enhancement of LY294002 concentrations (r=-0.953); compared with control group, the apoptosis rate of platelets in LY294002 group was enhanced significantly(P<0.05),while the apoptosis rate of platelets in LY294002+APS group significantly was reduced(P<0.05) as compare with LY294002 group, which suggest that APS has an anti-apoptotic effect on the cryopreserved platelets. APS decreased the expression of Caspase-3 and inhibited the reduction of mitochondrial membrane potential induced by LY294002, moreover, APS could increase the activation of PI3K /AKT pathway in Plt.@*CONCLUSION@#APS has an anti-apoptotic effect on the cryopreserved platelets through activating the PI3K /AKT pathway, decreasing the expression of apoptosis protease Caspase-3 and inhibiting the reduction of MMP.
Subject(s)
Angelica , Apoptosis , Blood Platelets , Chromones , Morpholines , Phosphatidylinositol 3-Kinases , Polysaccharides , Proto-Oncogene Proteins c-akt摘要
Prostaglandin (PG) E plays critical roles during pregnancy and parturition. Emerging evidence indicates that human labour is an inflammatory event. We sought to investigate the effect of PGE on the output of proinflammatory cytokines in cultured human uterine smooth muscle cells (HUSMCs) from term pregnant women and elucidate the role of subtypes of PGE receptors (EP, EP, EP and EP). After drug treatment and/or transfection of each receptor siRNA, the concentrations of inflammatory secreting factors in HUSMCs culture medium were detected by the corresponding ELISA kits. The results showed that, PGE increased interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFα) output, decreased chemokine (c-x-c motif) ligand 8 (CXCL8) output in a dose-dependent manner, but had no effect on IL-1β and chemokine (c-c motif) ligand 2 (CCL-2) secretion of HUSMCs. EP/EP agonist 17-phenyl-trinor-PGE stimulated IL-6 and TNFα whilst suppressing IL-1β and CXCL8 output. The effects of 17-phenyl-trinor-PGE on IL-1β and CXCL8 secretion were remained whereas its effect on IL-6 and TNFα output did not occur in the cells with EP knockdown. The stimulatory effects of 17-phenyl-trinor-PGE on IL-6 and TNFα were remained whereas the inhibitory effects of 17-phenyl-trinor-PGE on IL-1β secretion was blocked in the cells with EP knockdown. Either of EP and EP agonists stimulated IL-1β and TNFα output, which was reversed by EP and EP siRNA, respectively. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked EP/EP modulation of TNFα and CXCL8 output. PI3K inhibitor LY294002 and P38 inhibitor SB202190 blocked 17-phenyl-trinor-PGE-induced IL-1β and IL-6 output, respectively. The inhibitors of adenylyl cyclase and PKA prevented EP and EP stimulation of IL-1β and TNFα output, whereas PLC and PKC inhibitors blocked EP- and EP-induced TNFα output but not IL-1β output. Our data suggest that PGE receptors exhibit different effects on the output of various cytokines in myometrium, which can subtly modulate the inflammatory microenvironment in myometrium during pregnancy.
Subject(s)
Female , Humans , Pregnancy , Cells, Cultured , Chromones , Pharmacology , Cytokines , Metabolism , Imidazoles , Pharmacology , Inflammation , Morpholines , Pharmacology , Myocytes, Smooth Muscle , Cell Biology , Myometrium , Cell Biology , Phosphatidylinositol 3-Kinases , Pyridines , Pharmacology , Receptors, Prostaglandin E , Physiology摘要
This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR) control group received DMSO (1 µL/kg) immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg) were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg) and LY294002 (10 µM), L-NAME (10 μM), or norbinaltorphimine (norBIN, 1 μM) after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF) were also measured. The phosphorylation of AKT (p-AKT) was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE) and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.
Subject(s)
Animals , Male , Rats , Cerebral Arteries/drug effects , Brain Ischemia/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Diterpenes, Clerodane/pharmacology , Signal Transduction , Cerebral Arteries/physiopathology , Brain Ischemia/drug therapy , Morpholines/administration & dosage , Chromones/administration & dosage , Rats, Sprague-Dawley , Cyclic GMP/cerebrospinal fluid , Cyclic GMP/metabolism , NG-Nitroarginine Methyl Ester , Diterpenes, Clerodane/antagonists & inhibitors , Disease Models, Animal , Naltrexone/administration & dosage , Naltrexone/analogs & derivatives摘要
BACKGROUND@#Chemotherapy is the most important method for cancer treatment. However, chemotherapy induced nausea and vomiting (CINV) has a profound effect on patients. In recent years, there have been new antiemetic drugs, such as aprepitant. We review the curative effect of aprepitant with tropisetron and dexamethasone for prevention of nausea and vomiting in patients receiving Cisplatin chemotherapy.@*METHODS@#Observation is divided into three stages. Whole study phase (0-120 h after chemotherapy administration), acute phases (0-24 h), and delayed phase (24 h-120 h). The primary endpoints were complete response (CR) and complete prevention (CP) during the three different study phase.@*RESULTS@#In the whole study phase, 86.02% of patients achieved CR; in acute phases and delayed phases were 89.25%, 87.1%, respectively. CP were 46.22%, 83.87%, 45.16%, respectively. Anti-CINV effect was significantly associated with age distribution (P=0.008).@*CONCLUSIONS@#Aprepitant with tropisetron and dexamethasone prevented effectively CNIV for patients receiving Cisplatin chemotherapy. This combination could improve the quality of life and the compliance of patient with chemotherapy.
Subject(s)
Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Antineoplastic Agents , Aprepitant , Cisplatin , Morpholines , Pharmacology , Nausea , Quality of Life , Vomiting摘要
OBJECTIVE@#: To investigate the effect of nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866 on the migration of human non-small cell cancer A549 cells and related mechanism.@*METHODS@#: The inhibition effect of FK866 on A549 cells was tested by MTT assay. A549 cells were treated with 1.0 and 10.0 nmol/L FK866, and the cell migration was evaluated by modified wound scratch assay. The mRNA expression of E-cadherin and vimentin was detected by real-time RT-PCR, and the expression of ERK1/2 and pERK1/2 was determined by Western blotting.@*RESULTS@#: FK866 inhibited the proliferation of A549 cells in a time-and concentration-dependent manner; after treatment for 72 h, the IC of FK866 was 9.55 nmol/L. When 1.0 nmol/L or 10.0 nmol/L FK866 was continuously applied 48 h before and 48 h after a scratch was made in wound scratch assay, the migration of A549 cells was significantly inhibited. However, when the FK866 was applied only 48 h after the scratch, the migration of A549 cells was inhibited by 10.0 nmol/L but not by 1.0 nmol/L FK866. The mRNA expression of E-cadherin and vimentin, and the activated ERK1/2 were significantly increased after 1.0 nmol/L FK866 treatment for 72 h. The pretreatment with nicotinamide adenine dinucleotide (NAD) precursor nicotinamide mononucleotide(1.0 mmol/L) or ERK1/2 inhibitor U0126 (10.0 μmol/L) reversed the up-regulation of E-cadherin and vimentin expression induced by FK866.@*CONCLUSIONS@#s: Low concentration of FK866 decreases the migration of A549 cells through the inhibition of NAD level, activation of ERK1/2 and up-regulation of E-cadherin expression. However, it also up-regulates the expression of vimentin, indicating that it may have dual effects on the migration of tumor cells.
Subject(s)
Humans , A549 Cells , Cadherins , Genetics , Cell Movement , Gene Expression Regulation , Morpholines , Pharmacology , Neurokinin-1 Receptor Antagonists , Pharmacology , Nicotinamide Phosphoribosyltransferase , Piperazines , Pharmacology , Vimentin , Genetics摘要
Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.
Subject(s)
Animals , Male , Rabbits , Peptides/pharmacology , Venoms/pharmacology , Protective Agents/pharmacology , Fatty Liver/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/drug effects , Blood Glucose/analysis , Body Weight/drug effects , In Vitro Techniques , Gene Expression Regulation/drug effects , Morpholines/metabolism , Chromones/metabolism , Disease Models, Animal , Eating/drug effects , Enzyme Inhibitors/metabolism , Fatty Liver/pathology , Diet, High-Fat , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics , Exenatide , Insulin/blood , Malondialdehyde/analysis , Obesity/metabolism摘要
Advanced prostate cancer, especially at the castration-resistant stage, remains incurable clinically and, therefore, urgently requires new therapeutics for the patients. PI3K is a family of critical cell signal transduction molecules and their over-activation is an important factor in cancer development and progression. It has been demonstrated that class IA PI3K p110 is drastically overexpressed in prostate cancer and involved in androgen receptor-mediated gene expression and castration-resistant progression and regarded as a potential therapeutic target for prostate cancer. Several p110-specific inhibitors have been reported recently and two of them, GSK2636771 and AZD8186, are being tested in clinical trials.
Subject(s)
Humans , Male , Aniline Compounds , Therapeutic Uses , Chromones , Therapeutic Uses , Imidazoles , Therapeutic Uses , Morpholines , Therapeutic Uses , Neoplasm Proteins , Phosphatidylinositol 3-Kinases , Metabolism , Phosphoinositide-3 Kinase Inhibitors , Prostatic Neoplasms, Castration-Resistant , Drug Therapy , Protein Kinase Inhibitors , Therapeutic Uses摘要
<p><b>BACKGROUND</b>Nonanesthetic colonoscopy is popular in clinical practice in China. However, intestinal spasms often result in a prolonged examination time, increased operating difficulties, decreased polyp detection rate, and failure to complete the procedure clinically. Therefore, exploring alternative approaches that can reduce the pain in patients during colonoscopy is of utmost importance, and finding the optimal preoperative administration to improve the quality of nonanesthetic colonoscopy is also necessary. This study aimed to investigate the effects of the prophylactic administration of pinaverium bromide before colonoscopy and the effects of pinaverium bromide alone at different time points or combined with scopolamine butylbromide.</p><p><b>METHODS</b>A randomized controlled trial was performed on a cohort of 1000 patients who underwent colonoscopy in outpatient clinic of Wuhan Union Hospital. The patients were randomly assigned to the following groups: Group A, given oral pinaverium bromide (100 mg, three times a day) one day before examination combined with intramuscular injection of scopolamine butylbromide (20 mg) 10 min before colonoscopy; Group B0, given pinaverium bromide alone on the day of colonoscopy (100 mg, three times a day); Group B1, given pinaverium bromide alone (100 mg, three times a day) one day before colonoscopy; Group B2, given pinaverium bromide alone (100 mg, three times a day) two days before colonoscopy; and Group C, given scopolamine butylbromide alone (20 mg) before colonoscopy. The successful rate of colonoscopy, procedure time, degree of abdominal pain, and polyp detection rate were recorded and compared among all groups.</p><p><b>RESULTS</b>The successful rate of colonoscopy in Group B1(82.0%) and Group B2(83.0%) was significantly higher than that in Group B0(62.0%, all P < 0.01). The time to reach the ileocecal region in Group B1and Group B2were lower than those in Group B0(all P < 0.05). However, no significant differences were observed in polyp detection rate between Group B1(24.0%) or Group B2(26.0%), and Group B0(22.4%, all P > 0.05). Furthermore, there were no significant differences in the various parameters examined between Group B1and Group B2(P > 0.05). The successful rate of colonoscopy in Group A (92.0%) was significantly higher than that in Group B1(82.0%) and Group C (80.0%; both P < 0.05). Moreover, the time for the colonoscope to reach the ileocecal region in Group A were markedly shorter as compared to those in Group B1 and Group C (P < 0.05). The polyp detection rate in Group A was 32.0%, significantly higher than that in Group B1(24.0%, P < 0.05) and Group C (24.2%, P < 0.05).</p><p><b>CONCLUSION</b>Administration of pinaverium bromide alone one day before examination was beneficial to relieve symptoms of abdominal pain during nonanesthetic colonoscopy. In addition, therapeutic effects were improved when pinaverium bromide administration was combined with intramuscular injection of scopolamine butylbromide. Therefore, the combined use of pinaverium bromide with scopolamine butylbromide might have great application value to improve the quality of nonanesthetic colonoscopy in the preoperative preparation.</p>
Subject(s)
Adult , Female , Humans , Male , Middle Aged , Abdominal Pain , Colonoscopy , Methods , Double-Blind Method , Morpholines , Therapeutic Uses , Preoperative Period摘要
<p><b>OBJECTIVE</b>To observe the protective effects of Tongxinluo (TXL) on apoptosis of rat cardiac microvascular endothelial cells (RCMECs) resulting from homocysteine (Hcy) induced endoplasmic reticulum stress (ERS), and to determine the signaling pathway behind its protection.</p><p><b>METHODS</b>Primary cultured RCMECs were isolated from neonatal rats using tissue explant method. The morphology of RCMECs was observed using inverted microscope, identified and differentiated by CD31 immunofluorescence method. Selected were well growing 2nd-4th generations of RCMECs. The optimal action time was determined by detecting the expression of glucose regulated protein 78 (GRP78) using immunofluorescence method. In the next experiment RCMECs were divided into 5 groups, i.e., the blank control group, the Hcy induced group (Hcy 10 mmol/L, 10 h), the Hcy + TXL group (Hcy 10 mmol/L + TXL 400 µg/mL), the Hcy +LY294002 group (Hcy 10 mmol/L + LY294002 5 µmol/L, LY294002 as the inhibitor of PI3K), the Hcy + LY294002 + TXL group (Hcy 10 mmol/L + LY294002 5 µmol/L + TXL 400 µg/mL). The apoptosis rate of RCMECs was detected by flow cytometry. mRNA and protein expressions of GRP78, C/ EBP homologous protein (CHOP), and cysteinyl aspartate specific proteinase-12 (caspase12) were detected by real-time reverse transcription PCR (RT-PCR) and Western blot respectively. Expression levels of phosphorylation of phosphatidylinositol 3-kinase (P-PI3K), total phosphatidylinositol 3-kinase (T- P13K) , phosphorylation of kinase B (P-Akt) , and total kinase B (T-Akt) were detected by Western blot.</p><p><b>RESULTS</b>Ten hours Hcy action time was determined. Compared with the blank control group, the apoptosis rate was increased (22.77%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were increased, protein expressions of P-PI3K and P-Akt,ratios of P-PI3K/T-PI3K and P-Akt/T-Akt were decreased in the Hcy induced group (P < 0.05, P < 0.01). Compared with the Hcy induced group, the apoptosis rate was decreased (10.17%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were decreased, and expression levels of P-PI3K, P-Akt, P-PI3K/T-PI3K, and P-Akt/T-Akt were increased in the Hcy + TXL group (P < 0.05, P < 0.01). Compared with the Hcy + TXL group, the apoptosis rate was increased (17.9%), mRNA and protein expressions of GRP78, CHOP, and Caspase-12 were increased, expression levels of P-PI3K and P-Akt, ratios of P-PI3K/T-PI3K and P-Akt/T-Akt were decreased in the Hcy + TXL + LY294002 group (P < 0.05, P < 0.01).</p><p><b>CONCLUSION</b>TXL could inhibit the apoptosis of RCMECs resulting from Hcy-induced ERS and its mechanism might be associated with activating PI3K/Akt signaling pathway.</p>
Subject(s)
Animals , Rats , Apoptosis , Caspase 12 , Metabolism , Cells, Cultured , Chromones , Pharmacology , Drugs, Chinese Herbal , Pharmacology , Endoplasmic Reticulum Stress , Endothelial Cells , Morpholines , Pharmacology , Myocardium , Cell Biology , Phosphatidylinositol 3-Kinases , Metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt , Metabolism , Signal Transduction , Transcription Factor CHOP , Metabolism摘要
The aim of the present study was to investigate the mechanism of the inhibitory effect of luteolin on the proliferation of breast cancer cells induced by epidermal growth factor (EGF) in vitro. MTT assay was used to detect the inhibitory effect of luteolin on the proliferation of MCF-7 and MDA-MB-231 cells as well as the effect on the proliferation of MCF-7 cells induced by EGF. Western blotting was used to detect the effects of luteolin on the expression of epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (Erk) 1/2 and signal transducers and activators of transcription-3 (STAT3) in MCF-7 cells induced by EGF. The results showed that luteolin could significantly inhibit the proliferation of MCF-7 and MDA-MB-231 cells, and the inhibitory effect on MCF-7 cells was more prominent. Moreover, luteolin could inhibit the proliferation of MCF-7 cells induced by EGF. Western blotting results showed that luteolin and AG1478 (an inhibitor of EGFR signaling) could inhibit the expression of p-EGFR and p-STAT3 in MCF-7 cells induced by EGF. Luteolin, LY294002 (an inhibitor of Akt signaling) and PD98059 (an inhibitor of Erk1/2 signaling) could inhibit the expression of p-Akt and p-Erk1/2 respectively in MCF-7 cells induced by EGF. Our data suggest that luteolin may inhibit EGF-induced activities of EGFR signaling pathway in human breast cancer cell lines, and PI3K/Akt, MAPK/Erk1/2, STAT3 signal pathways may be the major pathways that mediate the inhibitory effect of luteolin on EGFR signaling. Overall, our results may provide a theoretical foundation for the development of luteolin as anti-tumor drug.
Subject(s)
Humans , Breast Neoplasms , Cell Line, Tumor , Cell Proliferation , Chromones , Epidermal Growth Factor , Luteolin , MAP Kinase Signaling System , Mitogen-Activated Protein Kinase 1 , Mitogen-Activated Protein Kinase 3 , Morpholines , Phosphatidylinositol 3-Kinases , Quinazolines , ErbB Receptors , Tyrphostins摘要
<p><b>OBJECTIVE</b>To observe morphological changes of enteric nervous system (ENS)-interstitial cells of Cajal (ICC)-smooth muscle cell (SMC) structure injury in deep muscle nerve plexus offunctional dyspepsia (FD) rats, and the repair of Shuwei Decoction (SD) on it, and to explore its effecton FD.</p><p><b>METHODS</b>Totally 72 rats were randomly divided into the control group, the model group, the lowdose SD group, the medium dose SD group, and the high dose SD group, the Mosapride group, 12 ineach group. Rats in the low dose SD group, the medium dose SD group, and the high dose SD group were intragastrically fed with SD at 0.767, 1.534, 3.068 g/mL, respectively. Rats in the Mosapride group were intragastrically fed with Mosapride (1.37 mg/kg). FD rat model with Gan depression Pi deficiency syndrome (GDPDS) was established using complex pathogenic factors. Corresponding liquors were respectively administered to rats in corresponding groups from the 3rd day after modeling. Distilled water(10 mL/kg) was administered to rats in the control group and the model group, once per day for 14 successive days. Rats were sacrificed and small intestine tissues collected for observing ENS-ICC-SMC structure injury using immunofluorescence double labeling, laser scanning confocal microscope, and transmission electron microscope at day 15. Repair of SD on it was also observed.</p><p><b>RESULTS</b>ENS-ICC SMC structure was incomplete, with obvious injury in mutual link of ICC, ICC, SMC, and connecting structure. ENS-ICC-SMC structure was more complete in high, medium, and low dose SD groups, with close link of ICC and SMO. Their connecting structures were in good conditions.</p><p><b>CONCLUSION</b>SD could keep the integrity of ENS-ICC-SMC structure by promoting regeneration and morphology of ICC, thereby, improving gastrointestinal movement disorder and showing therapeutic effect on FD.</p>
Subject(s)
Animals , Rats , Benzamides , Pharmacology , Drugs, Chinese Herbal , Pharmacology , Dyspepsia , Drug Therapy , Enteric Nervous System , Interstitial Cells of Cajal , Morpholines , Pharmacology , Muscle, Smooth , Random Allocation摘要
Cancer stem cells (CSCs) have tumor initiation, self-renewal, metastasis and chemo-resistance properties in various tumors including colorectal cancer. Targeting of CSCs may be essential to prevent relapse of tumors after chemotherapy. Phosphatidylinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signals are central regulators of cell growth, proliferation, differentiation, and apoptosis. These pathways are related to colorectal tumorigenesis. This study focused on PI3K and mTOR pathways by inhibition which initiate differentiation of SW620 derived CSCs and investigated its effect on tumor progression. By using rapamycin, LY294002, and NVP-BEZ235, respectively, PI3K and mTOR signals were blocked independently or dually in colorectal CSCs. Colorectal CSCs gained their differentiation property and lost their stemness properties most significantly in dual-blocked CSCs. After treated with anti-cancer drug (paclitaxel) on the differentiated CSCs cell viability, self-renewal ability and differentiation status were analyzed. As a result dual-blocking group has most enhanced sensitivity for anti-cancer drug. Xenograft tumorigenesis assay by using immunodeficiency mice also shows that dual-inhibited group more effectively increased drug sensitivity and suppressed tumor growth compared to single-inhibited groups. Therefore it could have potent anti-cancer effects that dual-blocking of PI3K and mTOR induces differentiation and improves chemotherapeutic effects on SW620 human colorectal CSCs.